Mitochondrial apoptosis markers in the progression of endometrioid adenocarcinoma.

Abstract

e17625 Background: Endometrial cancer (EC) is one of the most common malignancies of the female reproductive system. The incidence of EC is steadily increasing by approximately 1% annually, accounting for 20–30% of female genital tract tumors. Metabolic reprogramming is recognized as an emerging hallmark of malignant cells. Within these cells, the two critical mitochondrial functions—respiration and apoptosis—are in constant conflict yet intrinsically linked. Apoptosis can function not only as a tumor suppression mechanism but also exhibit pro-oncogenic properties, promoting the emergence and maintenance of aggressive tumors. Currently, research on the mitochondrial apoptotic pathway primarily utilizes human cancer cell lines, while studies examining mitochondria isolated directly from patient tumor tissues remain scarce. The aim of this study was to investigate changes in apoptotic markers within the mitochondria of endometrioid adenocarcinoma (EA) cells in gynecologic oncology patients, depending on the tumor grade. Methods: The study included patients who underwent surgical treatment for stage T1N0M0 EA (n=42) and uterine fibroids (n=14). The EA cohort consisted of 16 patients with well-differentiated (G1), 12 with moderately differentiated (G2), and 14 with poorly differentiated (G3) tumors. The mean age was 60.8±2.9 years for EA patients and 49.4±2.5 years for those with fibroids. Patients did not receive neoadjuvant therapy. Concentrations of cytochrome C (ng/mg protein), AIF (pg/mg protein), Bcl-2 (pg/mg protein), and calcium (μM/mg protein) were determined in the mitochondrial fraction of EA cells, fibroids, and intact uterine tissue using enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using parametric and nonparametric tests with correction for multiple comparisons. Results: A decrease in tumor cell differentiation was associated with reduced mitochondrial calcium levels; in G2 and G3 tumors, levels were on average 2.0 times lower than in the mitochondria of intact uterine tissue. Bcl-2 content in G3 tumor mitochondria was significantly higher (1.9 times on average) compared to the respective values in G1 and G2 (p<0.05). Cytochrome C levels in G1 were 2.2 times higher than in G2 and 1.9 times higher than in G3 (p<0.05). Mitochondria of G3 cells exhibited the highest AIF values, which were 2.1 times higher than in intact tissue and 1.9 times higher than in fibroid mitochondria (p<0.05). Conclusions: It is hypothesized that the suppression of apoptosis in endometrioid adenocarcinoma mitochondria is driven by increased Bcl-2 accumulation and decreased calcium levels, accompanied by the retention of cytochrome C and AIF, suggesting metabolic reprogramming necessary for cell survival. The magnitude of biochemical alterations in EA mitochondria increases with the tumor grade, likely contributing to the enhanced aggressiveness of the tumor.